Journal of Pediatric Gastroenterology and Nutrition

49:639641 # 2009 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and
North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

Case Report

Autoimmune Hepatitis in a Child With Chronic Hepatitis B

Virus Infection

Narayanan Venkatasubramani, ySara Szabo, and
Steven L. Werlin
of Pediatrics, Division of Pediatric Gastroenterology, and {Department of Pathology;
Medical College of Wisconsin and Childrens Hospital of Wisconsin, Milwaukee

Department

Chronic hepatitis B virus (HBV) infection is a major

health problem affecting 400 million people around the
world. An estimated 200,000 new cases of HBV occur
annually, and 1 to 1.25 million people are infected with
chronic hepatitis B virus in the United States (1). Vertically transmitted HBV is rare in the United States and
Western Europe but common in Asia and Eastern Europe.
About 90% of children with vertically transmitted HBV
infection become chronic carriers (2). At least 20% to
30% of carriers die from complications of cirrhosis and
hepatocellular carcinoma (HCC) (3,4).
Autoimmune hepatitis (AIH) is a rare disease in
children, with a frequency of 11% to 23% among children with chronic liver disease (5). AIH accounts for
about 6% of liver transplantations in the United States.
Without treatment, approximately 50% of adult patients
with severe AIH die in 5 years; children with treatment
have a favorable long-term outcome, with a transplantfree survival rate of 90% over a 10-year follow-up period
(6). A number of viruses have been implicated in the
pathogenesis of AIH such as hepatitis A and Epstein-Barr
virus (7,8).
Coexistence of HBV and AIH has rarely been reported
in children (9). We report a 7-year-old girl with vertically
transmitted HBV infection and AIH who responded to a
combination of immunosuppression and antiviral therapy
and discuss the management strategies of this rare cooccurrence.

active or chronic liver disease such as pruritus, jaundice,

bleeding, xanthomas, ascites, or weight loss. Her appetite
and growth were normal. Review of systems and previous
medical history was unremarkable. Family history was
not available. Physical examination was normal; in
particular, she was jaundice free and her liver and spleen
were not enlarged. She was positive for HBsAg and
HBeAg and negative for HBsAb and HbeAb. HBVDNA titer was 4  107 copies/mL. Her alanine transaminase (ALT) varied between 102 and 124 IU/mL during
the next 3 years (Fig. 1). At age 7, during yearly followup, she was well, without signs or symptoms of liver
disease. Her growth was normal. Physical examination
was normal. Her ALT was 650 IU/mL. HBV-DNA was
detected at 1.7  107copies/mL. Her bilirubin and coagulation parameters were normal. Serologies for hepatitis
A, C, and D; cytomegalovirus; and Epstein-Barr virus
were negative. Ceruloplasmin was normal. Alpha 1 antitrypsin Pi type was MM. Her antinuclear antibody and
antismooth muscle antibody titers were 80 (normal <40)
and 26 (normal <20), respectively. Anti-liver kidneymicrosomal and antimitochondrial antibodies were not
detected. Liver biopsy showed active chronic HBV
associated with features of AIH, including a mixed portal
and periportal inflammatory infiltrate with numerous
plasma cells, mild portal fibrosis with focal incomplete
bridging, and focal mild lobular fibrosis (Fig. 2). Immunostaining for HBV surface antigen showed large areas of
positive cells with predominantly cytoplasmic and focal
membranous staining. The diagnostic interpretation was
AIH developed on a background of vertically transmitted
HBV, now in a markedly active chronic phase. Transaminases normalized after 1 month of prednisone (20 mg/d)
treatment. Prednisone was tapered over the next month,
and azathioprine (50 mg/d) was given as a steroid-sparing
agent for the next 10 months. One month after starting azathioprine, the HBV viral load increased from
0.08  107 copies/mL to 0.3  107 copies/mL, hence adefovir 10 mg once a day was started for concerns of HBV
reactivation and was continued for a total of 9 months.

CASE REPORT
A 4-year-old girl, recently adopted from China, was
referred for evaluation of a positive hepatitis B surface
antigen (HBsAg) test. She had no signs or symptoms of
Received July 18, 2008; accepted August 5, 2008.
Address correspondence and reprint requests to Steven L. Werlin,
MD, Department of Pediatrics, The Medical College of Wisconsin,
8701 Watertown Plank Road, Milwaukee, WI, 53226 (e-mail: swerlin
@mcw.edu).
The authors report no conflicts of interest.

639

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640

VENKATASUBRAMANI ET AL.
DISCUSSION

FIG. 1. Chronological presentation of alanine transaminase/

hepatitis B virus level and treatment of the case.

Within 1 month, the DNA viral load decreased to

<100 copies/mL with a normal ALT level. All her medications were discontinued after 11 months of treatment.
One month later, her ALT and HBV DNA level increased
to 182 IU/mL and 6000 copies/mL, respectively. Her HBV
DNA and ALT level became normal without any change in
management. The patient remains well 16 months after all
medications were discontinued. Repeat liver biopsy was
refused.

FIG. 2. Liver biopsy showing active chronic hepatitis B virus

(HBV) with associated features of autoimmune hepatitis. (A and
B) Mixed portal and periportal inflammatory infiltrate with numerous plasma cells (hematoxylin and eosin stain). (C) Focal lobular
inflammation with individual hepatocyte necrosis (hematoxylin and
eosin stain). (D) Immunohistochemical stain for HBV surface
antigen with a predominantly cytoplasmic and focally membranous staining (insert: positive control).

HBV infection is a global public health problem, with

an estimated 1 million deaths per year worldwide from
HBV-related complications (1). Vertical HBV infection is
usually a benign condition during childhood; however, at
least 20% to 30% of adults with vertically transmitted
HBV infection die from cirrhosis or HCC. Several risk
factors such as high HBV DNA levels, positive HBeAg
status, and abnormal ALT levels have been identified to
predict long-term outcomes such as cirrhosis and HCC in
adults (10).
The currently available therapies are less likely to
benefit pediatric patients because most children with
vertically transmitted HBV infection have only minimally elevated serum ALT levels. The treatment of
vertically transmitted HBV in children with minimally
elevated serum transaminase levels is controversial.
Previous studies have found that perinatal HBV infection
responds poorly to antiviral therapy. However, a pilot
study showed treatment with lamivudine and interferonalpha resulted in complete viral clearance in 17% of
23 children with vertically transmitted HBV infection
associated with high viral loads and normal ALT levels
(11). The current American Association for the Study of
Liver Diseases (AASLD) guidelines recommend treating
HBeAg-positive children if the ALT levels are greater
than 2 times normal for more than 6 months (12). A
prospective cohort study in Taiwan reported that, independent of other factors, high viral replication may
predict poor long-term disease outcome (13). These
authors suggest that the critical goal in the treatment
of vertical chronic HBV is to suppress the HBV DNA to
very low or undetectable levels. This viral suppression is
important to prevent cirrhosis and HCC. All HBVinfected individuals should be checked for coinfection
with HIV, hepatitis C virus, and hepatitis D virus.
AIH is a chronic, necroinflammatory hepatitis characterized by the presence of autoantibodies against liverspecific and nonliver-specific antigens, increased
immunoglobulin G levels, and a dense mononuclear
infiltrate in the portal tracts (14). The initial treatment
of choice is steroid administration followed by maintenance azathiopurine therapy (15).
Viral infection has been proposed to trigger AIH in a
small percentage of these patients (7). One possible
explanation is the stimulation of B-lymphocytes specific
for normal liver antigens by activated T-lymphocytes
against HBV-infected liver cells leading to the production
of autoimmune antibodies and subsequent AIH (16,17).
Only 3 cases of the coexistence of HBV infection and
AIH have been reported, and only 1 was a child. An adult
case report mentioned the concurrent development of
AIH and the presence of a mutant HBeAg-negative virus
(18). Treatment with prednisone did not improve the
serum transaminase levels and viral load. Adenine

J Pediatr Gastroenterol Nutr, Vol. 49, No. 5, November 2009

Copyright 2009 by Lippincott Williams & Wilkins.Unauthorized reproduction of this article is prohibited.

AUTOIMMUNE HEPATITIS IN A CHILD WITH CHRONIC HEPATITIS B VIRUS INFECTION

arabinoside monophosphate treatment allowed simultaneous inhibition of virus multiplication and remission
of AIH. In another adult case, AIH developed after acute
HBV infection (19). The patient cleared the virus spontaneously, and the symptoms of AIH improved after
immunosuppression with prednisone and azathioprine.
The only pediatric case report raised the possibility of
persistent HBV infection triggering the development of
AIH (9). The patient was started on prednisone, and this
was associated with an increase in HBV DNA levels.
Prednisone was tapered, and lamivudine was initiated
with a subsequent decrease in viral copies and ALT level.
We report the second pediatric case of the rare development of AIH in the background of chronic HBV
infection. We considered the risk of immunomodulatory
treatment, including the possible exacerbation of active
chronic hepatitis with increasing HBV viral copy numbers (9). We opted for combined immunomodulatory and
antiviral therapy. We elected to treat the AIH first,
followed by adefovir to prevent exacerbation of HBV
during immunosuppression. The AASLD guidelines
recommend not using lamivudine as preferred first-line
therapy owing to concerns of the emergence of YMDD
mutation and viral resistance in adults. We decided to
treat with adefovir because of the relatively low development of resistant strains and for safety reasons. We
chose 10 mg of adefovir because this dose has been
shown to be effective in treating adult patients with
chronic HBV infection. Subsequently, a pediatric trial
showed adefovir is effective and safe in children aged
older than 12 years with chronic HBV infection but with
no significant decrease in HBV viral load in the younger
age group (20). However, our patient showed good
response to adefovir, with normalization of ALT level
and a decrease in the HBV viral load to undetectable
levels.
Conclusions
We report an unusual case of AIH after chronic HBV
infection. The dilemma in the treatment of our patient
was that immunomodulatory treatment of AIH might
exacerbate HBV infection. However, combined immunosuppression and antiviral therapy was successful in
normalizing the serum transaminase levels and suppressing HBV replication in a patient with coexistent HBV
and AIH.

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J Pediatr Gastroenterol Nutr, Vol. 49, No. 5, November 2009

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